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How The Animal Lost Its Sensor

Two-Component Systems are one of the major sensory systems used by bacteria to detect and respond to changes in both their outside environment, and their internal state. I cover them in more detail here, but just in summary they consist of two proteins,a sensor and a responder. The sensor senses the change, and activates the responder, which binds to the bacterial DNA and leads the production of a protein that will enact a suitable response.

Although Two-Component Systems (TCS) are found in all three superkingdoms of life (Archaea, Bacteria and Eukaryotes) they are suspiciously absent from the animal kingdom. Plants have them, as do fungi and several protazoa, but they just aren't present in animals. For this reason they've been looked into as potential antibiotic targets as knocking out the Two-Component Systems of most bacteria is fatal.

Why don't animals use TCSs? To answer this you have to start looking at the evolution of the system itself, because despite being nominally present in eukaryotes such as plants and fungi, TCSs are used very differently in bacteria and archaea. Bacteria use TCSs for sensing a wide variety of signals; stress, metabolism, nutrient regulation, chemotaxis, pathogen-host interactions etc. in eukaryotes on the other hand, they are used sparingly, for ethylene responses and photosensitivity in plants and osmoregulation in fungi and slime moulds.

Bacteria (especially soil bacteria which have a lot of environment to sense) can contain up to 50 TCSs although many internal parasite bacteria (with a lot less to sense) contain far less. The maximum for Archaea is around 20 TCSs. Eukaryote number drop right down, with only one in the yeast Saccharomyces cerevisiae (one sensor kinase and three response regulators). None have yet been found in any animal genomes, or in the few partial protist genomes sequences (although I doubt if anyone's had a complete scan through the protist genomes for them).

Comparing the TCSs of Bacteria, Archaea and Eukaryotes leads to the interesting conclusion that the bacterial and eukaryotic systems are far more closely related than the archaeal, and in fact are thought to be monophyletic (all evolved from a single common ancestor). In contrast, the archaeal TCSs appear to be polyphyletic and some archaea lack TCSs entirely. It's therefore thought that TCSs originated in bacteria and spread by horizontal gene transfer to both archaea and eukaryotes (until the eukaryotes developed a nuclear membrane). In eukaryotes very little further diversification took place, whereas the bacterial TCSs diversified widely, and occasionally passed new systems back to the archaea. I've tried to show this in the diagram below:

Diagram made by Lab Rat. Red arrows show the movement (straight arrows) and duplication (curved arrows) of TCS genes. No horizontal gene transfer can take place in eukaryotes after the nuclear membrane (well....it *can* do but very, very rare) although gene duplication may still have occurred.

The eukaryotic kingdom appears not to have contained very many of these TCS genes to start with, and the animal kingdom may just have lost the very few it possessed. This makes sense from the point of view of cellular control because while TCSs are very useful in the small genomed and non-nuclear membrane containing bacteria, it's less clear how useful they are in eukaryotes as a whole. Introducing a membrane around the nucleus makes it harder for proteins to get in and bind to the DNA, and introducing systems of membranes inside a far bigger cell makes it harder for a simple two-component system to sense what's going on. Added to which, cells inside a multicellular organism don't really need to sense what's going on, they get told what's going on by the surrounding cells and circulating hormones.

Whatever the reason though (and any other ideas would be welcomed, the above paragraph is mostly speculation) it is clear that despite this system being vital for bacteria it isn't used widely, or most likely at all, in animals. Research into this would be particularly useful against opportunistic pathogens which tend to have a large selection of two-component systems to allow them to adapt to different lifestyles depending on the conditions of their immediate environment.

4 comments:

Anonymous
said...

Weird that they're present in plants and fungi but not animal cells, (even if not to the same extent as in bacteria). If TCSs were absent in all eukaryotes it would make a lot more sense.What about choanoflagellates? They're closer to animals than fungi, aren't they?

I'd guess that for multi-cellular organisms they'd be less useful as the sorts of things they're sensing might often need to be "known" at the organism level, not it's individual and different cells - especially as differentiation increases.

Besides the fact that animal cells are already 'told what to do', eukaryotic cells are also biochemically less flexible than prokaryotic ones. Whereas a bacterium can 'decide' to use a different energy source, animal cells are pretty much fixed in what they can and cannot do, so they're faced less with 'do this or that' questions.

When animal cells respond to changes from the outside, hundreds of genes are up- or downregulated. So in addition, maybe the simple TCS system is too course-grained for complexer eukaryotic cells?

@cuco3: I don't think choanoflagellates use two-component systems either, although that was just from a quick search. They are definitely present in fungi and slime moulds though, and plants. As lucas mentions it might be that TCSs are used for simple responses, whereas most of the animal responses are more complex.

@lucas: Although animal cells are a lot less biochemically flexible, they still have plenty of choices about changing genes and the transcriptome, they just use different molecules to do it. It might be that the TCSs don't interact enough with each other to manage the highly interlocked network of animal signalling systems. More answers might come from looking closer at what roles the few TCSs left in eukaryotes play. :)